Chemical process for preparing 5h-dibenzo[a, d] cycloheptene



United States Patent 3,247,272 CHEMTCAL PROCESS FOR PREPARING H-DIBENZO[a,d]CYCLOHEPTENE Norman L. Wendler, Summit, and David Taub and Robert D. Hotfsommer, Jr., Metuchen, N.J., assignors to Merck & Co. Inc, Railway, N.J., a corporation of New Jersey No Drawing. Filed Oct. 28, 1963, Ser. No. 319,589 4 Claims. (Cl. 260668) This application is a continuation-in-part of our copendin application, Serial No. 227,727, filed October 2, 1962, now abandoned.

This invention relates to the preparation of hydrocarbons from the corresponding oxygenated compound and, more particularly, to the production of SH-dibenzo[a,d]cycloheptenes from the corresponding 5-oxygenated-SH-dibenzo [a,d 1 cycloheptene.

Many methods are known in the art for converting an oxygenated compound, e.g., a ketone or an alcohol, to the corresponding hydrocarbon. For example, several methods have been described in the literature for eliecting a conversion of S-oxygenated derivatives of SH-dibenzo[a,d]cycloheptenes, e.g., the SH-dibenzo[a,d]cyclohepten-S-ones and the 5-hydroxy-5H'dibenzo[a,d]cycloheptones, to the corresponding 5I- -dibenzo[a,d]cycloheptene. These methods generally involve a reduction procedure using such reducing agents as hydrazine (VVoltlF-Kishner) or Zn and HCl (Clernmenson). The yields obtained by these processes, however, are quite low due to the formation of dimeric by-products. A still further method involves the reaction of certain ketones with aluminum isopropoxide at temperatures of about 140 C. to about 145 C. While some improvement in the yield of hydrocarbon is obtained usin this procedure, it nevertheless is not as high as is desired. Consequently, several multi-step methods have evolved in which the ketone is reduced to the hydroxy intermediate which is then halogenated and the halogen removed reductively with metal combinations to produce the hydrocarbon. It will be apparent that the latter methods are lengthy and expensive.

Accordingly, an object of the present invention is to provide an improved method for the production of hydrocarbons from the corresponding ketones and alcohols in substantially higher yields than heretofore obtained.

Another object of this invention is to provide an improved one-step method for the preparation of 5H- dibenzo[a,d]cycloheptenes in quantitative yields and in an economical manner.

Other objects will be made apparent from the following, more detailed, description of the invention.

In accordance with the present invention, it has been found that by treating an oxygenated compound such as a ketone or alcohol, wherein the carbonyl or hydroxyl moiety is attached on both sides to an aromatic ring with an aluminum lower alkoxide, at elevated temperatures, reduction of the oxygenated compound to the corresponding hydrocarbon is very facile and results in the production of the hydrocarbon in essentially quantitative yields.

illustrative of the oxygenated compounds which may be reduced to the corresponding hydrocarbon in accordance with this invention are SH-dibenzo [.a,d]cyclohepten-5-one, 10,11 dihydro 5H -dibenzo[-a,d] cyclohepten 5- one, S-hydroxy-SH-dibenzo[a,d]cycloheptene one, 10,11- dihydro-S-hydroxy-SH-dibenzo a,d] cycloheptene, benzophenone, authraquinone, anthrone, xanthone and fluorenone.

The SH-dibenzo[a,d]cycloheptene and 10,11-dihydro- SH-dibenzo[a,d]cycloheptene compounds prepared by the process of the present invention are useful as interediates in that they may be readily converted to their 3,247,272 Patented Apr. 19, 1966 corresponding Salkali metal derivatives which, in turn, can be reacted with a tertiary aminopropyl halide to form the corresponding 5-(3-dialkylaminopropyl) derivative. These latter compounds, as well as the monodealkylated derivatives thereof, are useful in the treatment of mental health conditions, in that they are potent anti-depressants and serve as mood elevators or psychic energizers. The various other hydrocarbons which may be prepared by the present invention generally have known utility per se.

In carrying out the process of this invention, it is advantageous that the oxygenated compound to be reduced contain an aromatic ring on each side and adjacent to the reduction site, i.e., the carbonyl or hydroxyl moiety. In those instances where the carbonyl or hydroxyl group is not flanked by two aromatic nuclei, dehydration or rearrangement becomes dominant. As illustrated above, the aromatic rings may be similar or dissimilar, substituted or unsubstituted, homocyclic or heterocyclic. Additionally, the aromatic rings may be fused to a central ring containing the carbonyl or hydroxyl moiety. However, any substituents which may be attached to the aromatic rings need not be the same. 11- lustrative of such substituents are lower alkyl, lower alkenyl, trifiuoromethyl, amino, loweralkylamino, diloweralkylarnino, halogen, lower alkoxy, hydroxy, cyano, diloweralkylsulfarnoyl, loweralkylsulfonyl, mercapto, loweralkylmercapto, carbamoyl, loweralkylcarbamoyl and diloweralkylcarbamoyl.

The reduction of the oxygenated compound to the corresponding hydrocarbon is carried out at a temperature in the range of from C. to about 260 C. Preferably, however, the temperature is in the range of from about 200 C. to about 260 C. Temperatures greater than 260 C. may be employed providing, of course, that the reactants and end products are stable at such temperatures. However, the use of temperatures below 180 C. results in a substantial reduction in yield of the hydrocarbon. Consequently, the reduction must be carried out at a temperature of at least 180 C. in order to obtain a significantly greater yield of hydrocarbon with a concomitant reduction in the time and expense for carrying out the reaction.

The reduction of the oxygenated compound may be carried out in the presence of a substantially anhydrous, inert organic solvent. Suitable solvents include p-cymene and xylene. However, a solvent is not necessary in those instances where the substrate has a melting point in the presence of aluminum alkoxide. below 250 C. In fact, the reaction is preferably carried out in the fused state in the absence of a solvent.

In carrying out the reaction, it is preferred to employ an excess of the alkoxide although equimolar amounts of alkoxide and oxygenated compound can be employed with some sacrifice in the yield of hydrocarbon. Desirably, at least 3 moles of alkoxide per mole of oxygenated compound is employed. However, the particular amount of alkoxide employed in any given reaction will depend to some extent on the oxygenated compound to be reduced. Thus, in some instances it may be desirable to employ an even greater excess of the alkoxide. It will be readily appreciated by those in the art that the above applies to the reduction of those compounds containing a single reductive entity. Where more than one reductive entity is present, the amount of alkoxide employed should be adjusted accordingly. After completion of the reaction, the desired product is readily recovered employing conventional procedures.

As indicated hereinabove, the reduction of the oxygenated compound is effected employing an aluminum lower alkoxide. These alkoxides may be represented by the general formula:

Al(OR) wherein R is a lower alkyl radical containing from 2 to 5 carbon atoms. The alkyl substituent may be straight or branched chain, providing that the carbon atom which is attached to the oxygen atom contains at least one hydrogen atom attached thereto. The preferred alkoxide is aluminum isopropoxide.

The process of the invention is further illustrated by the following examples. not to be construed as in any way limiting the scope of the invention as defined in the claims.

EXAMPLE 1 Preparation f H -dibenz0 [a,d cycloheptene from 5 H -d ibenzo [a,'d 1 cycl0hepten-5 -one A 50 ml. round-bottom flask equipped with a stirring bar and distillation head is charged with 1.03 g. (0.005 mole) of SH-dibenzo[a,d]cyclohepten-5-one and 3.07 g. (0.015 mole) of aluminum isopropoxide. The reaction mixture is heated, with stirring, in an oil-bath to a bath temperature of 250-255 C., collecting any liquid which distills over. (Total distillate collected is 1.5 ml.) Heating is continued at this temperature until the reaction mixture has gone from a liquid melt to a solid. The solid residue is baked at 250 C. for an additional minutes, then cooled to room temperature and treated with dilute HCl (3.5 ml. conc. HCl in 17.5 ml. of water). After vigorous stirring with the acid for one hour, the mixture is filtered, washed with water, dried thoroughly and taken up in hot hexane. The hexane solution is filtered and taken to dryness in vacuo yielding a white crystalline residue of 960 mg. (100% yield) of SH-dibenzo[a,d]cycloheptene which melts at 123-128" C. and is not depressed on admixture with an authentic specimen. The I.R. spectrum of this product in Nujol and chloroform shows no hydroxyl or carbonyl absorption and is identical to the spectrum of an authentic sample.

Alternatively, the above ketone (1.03 g.) and aluminum isopropoxide is mixed in ml. of anhydrous xylene. The stirred reaction mixture is then heated (oil-bath temp. 250 C.) and the volatile material is removed by distillation, The residue is baked at 250 C. for 10 min utes and the product is isolated as above.

EXAMPLE 2 Preparation 0 f SH-dibenzo [a,d] cyclolzeptene from 5 -hydroxy-5H -di benzo [a,d cyclohep Iene A 50 ml. round-bottom flask equipped with a stirring bar and distillation head is charged with 1.04 g. (0.005 mole) of 5-hydroxy-5H-dibenzo[a,d]cycloheptene and 3.07 g. (0.015 mole) of aluminum isopropoxide. The reaction mixture is heated, with stirring, to an oil-bath temperature of 2 50-255 C. Heating is continued for 10 minutes after the reaction mixture has changed from a liquid to a solid, and an over-all total of 1.8 ml. of distillate is collected. The residue is cooled to room temperature and treated with dilute HCl (3.5 ml. conc. HCl

in 17.5 ml. of water) and ml. of chloroform. The aqueous layer is extracted with 15 ml. of chloroform and the combined chloroform extracts are washed successively with 15 ml. of water, 15 ml. of saturated salt .solution, and dried over anhydrous magnesium sulfate.

The dried solution is taken to dryness in vacno to yield 910 mg..(95% yield) of 5H-dibenzo[a,d]cycloheptene.

EXAMPLE 3 Preparation 0] 10,11 dihydro-SH-dibenzo-[a,d] cycloheptene from 1 0,11 -dihydro-5H-dibenzo [a,d] cyclohepten- 5 -One Following the procedure of Example 1, 1.04 g. of 10,11- dihydro-SH-dibenzo[a,d]cyclohepten-5-one is converted in essentially quantitative yield (95%) to 10,11-dihydro-5H- dibenzo[a,d]cycloheptene, M.P. 7274 C.

However, these examples are 4 EXAMPLE 4 Following the procedure of Example 2, '10,l1-hihydro- 5 hydroxy-5H-dibenzo[a,d] cycloheptene is converted to 10,1l-dihydro-SH-dibenzo[a,d] cycloheptene.

EXAMPLE 5 Preparation of diphenylm'ethane from benzo phenon 0.729 g. (4.0 millimoles) of benzophenone'and 2.45 g. (12.0 millimoles) of aluminum isopropoxide are charged to an oversized round-bottom flask fitted with a magnetic stirring bar and short side-arm adapter. fitted with a thermometer and connected to a condenser arranged for downward distillation. The reaction mixture is then heated in an oil-bath, with stirringpto a bath temperature of 250 C. The reaction mixture mel-ts' ca. 150180 C., with distillate starting to come over at about 200 C. The bath temperature is held at 250-260 C. to complete the reaction and remove the volatile materials. When the reaction is complete, the mixture foams up in a thick froth which, upon continued heating, sets up to a dry solid or semi-solid. The dry foam is then baked for about 15-30 minutes at 250 C. before cooling to room temperature. To the residue is added 20 ml. of 2.5 N HC1 and the mixture stirred for about 30 minutes. The mixture is then extracted with two portions of ether and the combined ether extract washed with saturated sodium chloride solution, dried over magnesium "Preparation of anthracene from anthraqul'none 2.08 g (10.0 millimoles) of anthraquinone and 12.26 g. (60.0 millimoles) of aluminum is-opropoxide are charged to an oversized round-bottom flask fitted with a magnetic stirring bar and short side-arm adapter. The adapter is fitted with a thermometer and connected to a condenser arranged for downward distillation. The reaction mixture is then heated in an oil-bath, with stirring, to a bath temperature of 250 C. The reaction mixture melts ca. ISO-180 C., with distillate starting to come over at about 200 C. The bath temperature is held at 250-260 C. to complete the reaction and remove the volatile materials. When the reaction is complete, the mixture foams up in a thick froth which, upon con-tinned heating, sets up to a dry solid or semisolid. The dry foam is then baked for about 15-30 minutes at 250 C. before cooling ,to room temperature. To the residue is added 45 ml. of 2.5 N HCl and the mixture stirred for about 20 minutes, and then filtered through Celite. The Celite is washed several times with water, followed by 3 washes with absolute ethanol, then extracted overnight with benzene in a Soxhlet extractor and the benzene extract taken to dryness in vacuo. Yield, 1.33 g. (75.5%).

EXAMPLE 7 Preparation of anthracene from anthrorle 1.94 g. (10.0 millimoles) of anthrone and 6.13 g. (30.0 millmoles) of aluminum isopropoxide are charged to an oversized round-bottom flask fitted with a magnetic stirring bar and short side-arm adapter. The adapter is fitted with a thermometer and connected to a condenser arranged for downward distillation. The reaction mix- ;ture is then heated in an oil-bath, with stirring, to a bath temperature of 250 C. The reaction mixture melts ca. ISO-180 C., with distillate starting to come over at about 200 C. The bath temperature is held at 250260 C.

to complete the reaction and remove the volatile materials. When the reaction is complete, the mixture foams up in athick froth which, upon-continued heating, sets The adapter is' up to a dry solid or semi-solid. The dry foam is then baked for about 15-30 minutes at 250 C. before cooling to room temperature. To the residue is added 30 ml. of 2.5 N HCl and the mixture stirred for about 30 minutes, and then filtered through Celite. The Celite is Washed with absolute ethanol and then extracted overnight with benzene in a Soxhlet extractor. The benzene extract is then taken to dryness in vacuo. Yield, 1.63 g. (91.5%).

EXAMPLE 8 Preparation of xanthene from xanthone 1.96 g. (10.0 millimoles) of xanthone and 6.13 g. (30.0 millimoles) of aluminum isopropoxide are charged to an oversized round-bottom flask fitted with a magnetic stirring bar and short side-arm adapter. The adapter is fitted with a thermometer and connected to a condenser arranged for downward distillation. The reaction mixture is then heated in an oil-bath, with stirring, to a bath temperature of 250 C. The reaction mixture melts ca. 150-180" C., with distillate starting to come over at about 200 C. The bath temperature is held at 250- 260 C. to complete the reaction and remove the volatile materials. When the reaction is complete, the mixture foams up in a thick froth which, upon continued heating, sets up to a dry solid or semi-solid. The dry foam is then baked for about 1530 minutes at 250 C. before cooling to room temperature. To the residue is added 30 ml. of 2.5 N HCl and the mixture stirred for about 1 hour and then extracted with two 20 m1. portions of ether. The combined ether extracts are washed with 10 ml. of water, then with 10 ml. of saturated sodium chloride solution and then dried over magnesium sulfate and taken to dryness in vacuo. Yield, 1.37 g. After recrystallization from hexane, yield 75%.

EXAMPLE 9 Preparation of fluorene from fluorenone 1.8 g. (10.0 millimoles) of fluorenone and 30.64 g. (150 millimoles) of aluminum isopropoxide are charged to an oversized round-bottom flask fitted with a magnetic stirring bar and short side-arm adapter. The adapter is fitted with a thermometer and connected to a condenser arranged for downward distillation. The reaction mixture is then heated in an oil-bath, with stirring, to a bath temperature of 250 C. The reaction mixture melts ca. ISO-180 C., with distillate starting to come over at about 200 C. The bath temperature is held at 250- 260 C. to complete the reaction and remove the volatile materials. When the reaction is complete, the mixture foams up in a thick froth which, upon continued heating, sets up to a dry solid or semi-solid. The dry foam is then baked for about -30 minutes at 250 C. before cooling to room temperature. To the residue is added 120 ml. of 2.5 N I-ICl and the mixture stirred for minutes. Residual traces of isopropanol are removed in vacuo and the residue chilled and filtered. The precipitate is washed twice with water, air dried and extracted with three portions of ether. The combined ether extracts is dried over magnesium sulfate and taken to dryness in vacuo. Yield, 1.63 g. This product is dissolved in boiling methanol and filtered to remove impurities.

6 Concentration of the mother liquor yields 920 mg. of product.

We claim:

1. A method for preparing a 5H-dibenzo[a,d]cycloheptene from the corresponding 5H-dibenzo[a,d]cyclo hepten-S-one which comprises treating the latter with an aluminum alkoxide at a temperature of at least C., said aluminum alkoxide having the formula Al(OR)- wherein R is a lower alkyl radical containing from 2 to 5 carbon atoms, providing, however, that the carbon atom which is attached to the oxygen atom of said alkoxide contains at least one hydrogen atom attached thereto.

3. A method for preparing a 5H-dibenzo[a,d]cycloheptene from the corresponding S-hydroxy-SH-dibenzo- [a,d]cycloheptene which comprises treating the latter with an aluminum alkoxide at a temperature of at least 180 C., said aluminum alkoxide having the formula Al(OR) wherein R is a lower alkyl radical containing from 2 to 5 carbon atoms, providing, however, that the carbon atom which is attached to the oxygen atom of said alkoxide contains at least one hydrogen atom attached thereto.

4. A method for preparing a 10,11-dihydro-5H-dibenzo[a,d]cycloheptene from the corresponding 10,11-dihydro 5 hydroxy-5H-dibenzo[a,d]cycloheptene which comprises treating the latter with an aluminum a koxide at a temperature of at least 180 C., said aluminum alkoxide having the formula wherein R is a lower alkyl radical containing from 2 to 5 carbon atoms, providing, however, that the carbon atom which is attached to the oxygen atom of said alkoxide contains at least one hydrogen atom attached thereto.

References Cited by the Examiner UNITED STATES PATENTS 2/ 1946 Doumani 260-448 5/1960 Arnold et al. 260448 OTHER REFERENCES Coffey et al.: Journal of the Chemical Society, July 1954, pages 2468 to 2470 relied upon.

DELBERT E. GANTZ, Primary Examiner.

ALPHONSO D. SULLIVAN, PAUL M. COUGHLAN,

Examiners. 

1. A MEMBER FOR PREPARING A 5H-DIBENZO(Q,D)CYCLOHEPTENE FROMTHE CORRESPONDING 5H-DIBENZO(A,D)CYCLOHEPTEN-5-ONE WHICH COMPRISES TREATING THE LATTER WITH AN ALUMINUM ALKOXIDE AT A TEMPERATURE OF AT LEAST 180*C., SAID ALUMINUM ALKOXIDE HAVING THE FORMULA 